tbuckley/cabot-search huggingface dataset:
TMIC-03. TARGETING THE COLLAGEN RECEPTOR DDR1 PROMOTES ANTI-GLIOMA IMMUNITY BY REMODELING COLLAGEN FIBER ARCHITECTURE
Authors: Syed M Faisal, Maria Varela, Andrea Comba, Anna Argento, Molly West, Emily Brumley, Clifford Abel II, Jarred Clewner, Brooklyn Stack, Santiago Haase, Anzar Mujeeb, Kaushik Banerjee, Marcus Barissi, Grace Abbud, Maria Castro, Pedro Lowenstein
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM), characterized by its aggressive nature and profound immunosuppression, poses a significant therapeutic challenge with limited treatment options. We previously demonstrated that targeting Col1α1 eradicates oncostreams and improves survival in murine models. However, the underlying mechanisms by which collagen reshapes the glioma tumor microenvironment (TME) remain unknown. Through RNA-seq analysis we identified that DDR1, a collagen receptor, is overexpressed in genetically engineered glioma mouse models (GEMMs) including NPA (NRAS/shp53/shATRX), and NPD (NRAS/shp53/PDGFβ), compared to healthy brain tissue. Pharmacological inhibition of DDR1 enhanced radiosensitivity, disrupted oncostreams in vitro, and ex vivo, imaged with time-lapse confocal microscopy. GEMMs of DDR1 knockdown (NRAS/shp53/shATRX/shDDR1) using the Sleeping Beauty transposase system significantly increased median survival by over 50%. Gene Ontology analysis of differentially expressed genes between wild-type and DDR1 knockdown gliomas revealed enrichment in immune reactivity, cytokine-chemokine activity, and extracellular matrix. Inhibition of DDR1 enhanced intratumoral infiltration of CD45+, CD8+, and CD3+ immune cells, accompanied by a decrease in the abundance of immune-suppressive cells, suggesting that gliomas exploit DDR1-mediated mechanisms to promote immunosuppression and facilitate tumor growth. We hypothesize that DDR1 in glioma impedes immune surveillance by promoting collagen fiber alignment, as evaluated using collagen-specific second-harmonic generation microscopy. Furthermore, analysis of human datasets demonstrated a negative correlation between DDR1 expression and CD8, suggesting DDR1’s role as a key regulator of immune surveillance in gliomas. Interestingly, when DDR1 knockdown gliomas were implanted in immune deficient mouse models, NSG (NOD-scid-IL2Rγnull) or CD8−/− immune-deficient mice, no significant differences in survival were observed, indicating DDR1 expression in glioma cells dampens anti-glioma immunity. In conclusion, we propose that DDR1 within glioma cells induces an immune-inhibitory TME, reprograms cytokine and chemokine profiles, and promotes collagen fiber alignment, thus inhibiting anti-glioma immunity. Our data highlight DDR1 as a promising therapeutic target, providing a novel avenue for GBM treatment with significant potential.
NCMP-27. CHARACTERISTICS OF RADIATION-INDUCED BRAIN TUMORS AFTER CRANIAL IRRADIATION
Authors: Shumpei Onishi, Fumiyuki Yamasaki, Yasuyuki Kinoshita, Takeshi Takayasu, Ushio Yonezawa, Akira Taguchi, Iori Ozono, Novita Ikbar Khairunnisa, Nobutaka Horie
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION The use of radiation therapy (RT) improves the outcome of cancer patients, while additionally increasing the risk of radiation-induced neoplasms in cancer survivors. The most common radiation-induced brain tumors (RIBT) are gliomas (RIG), meningiomas (RIM), and sarcomas (RIS). To investigate the characteristics of RIBT, we reviewed our case series and all relevant cases from the literature review. METHODS From our case series and literature review, we identified 920 RIBT patients who received cranial irradiation. We analyzed the age at irradiation for primary disease. The latency period from irradiation to the development of each RIBT and the median overall survival (OS) of RIBT were analyzed with Kaplan–Meier method. RESULTS Among RIBT patients, 23.2 % were irradiated less than 5 years, and 41.6% were irradiated in the first decade. The median age (interquartile range) at cranial irradiation were 9 (4.35 - 16) years in RIM patients, 9 (5 - 23) years in RIG patients, and 27 (13.7 - 40) years in RIS patients. The latency periods from irradiation to the development of RIM was significantly longer than RIG and RIS (RIM: 21 years, RIG: 9 years, RIS: 10 years; p &amp;lt; 0.0001). The median OS was significantly longer in patients with RIM than in those with RIG and RIS (RIM: not reached, RIG: 11 months, RIS 11 months; p &amp;lt; 0.0001). CONCLUSIONS RIG and RIS had a poor prognosis, while RIM had a relatively better prognosis. Because RIBTs develop more than a decade after cranial irradiation, long-term follow-up is crucial.
TMET-07. METABOLIC RISK FACTORS AND OUTCOMES IN PATIENTS WITH GLIOBLASTOMA
Authors: John Paul Aboubechara, Orwa Aboud
Journal: Neuro-Oncology (2023)

Abstract A growing body of evidence is beginning to implicate mutations in genes underlying cellular metabolism in the etiology of glioblastoma. The metabolic syndrome has been found to increase the risk of developing various systemic cancers, but it is not known how often the metabolic syndrome occurs in patients with glioblastoma or how it affects their clinical outcomes. Therefore, the purpose of this study is to test the hypothesis that the metabolic syndrome is a risk factor for developing glioblastoma and is associated with worse survival outcomes. A retrospective cohort study was conducted, consisting of patients at a single institution. Clinical records from 40 patients with glioblastoma IDH wild type were reviewed as part of this interim analysis—with plans to analyze 80 patients by study completion. Records included the patient’s diagnosis, progression free survival, overall survival, treatment, tumor molecular characteristics, blood pressure, body mass index, medications, and laboratory data. Our results demonstrate a trend that patients with the metabolic syndrome have worse overall survival compared to those who do not (16.7 months vs 8.1 months; p=0.069). Interestingly, hypertension (p=0.007), hyperglycemia (p = 0.044), and dyslipidemia (p = 0.041) were negatively associated with survival, while BMI was not. Furthermore, there was a significant negative association between overall survival and the number of metabolic risk factors that patients accumulate (i.e. BMI, HTN, etc.) (p=0.0038). However, our results demonstrate the prevalence of metabolic syndrome in GBM patients to be 30%, which is less than that of the general population, 35%. These interim results suggest that the metabolic syndrome is associated with worse survival in patients with glioblastoma IDH wild type, but that it is not a risk factor in the development of this cancer. These results support other work that has implicated metabolic dysregulation in the pathogenesis of glioblastoma.
TMIC-81. DECODING THE ROLE OF MICROENVIRONMENT ON DISTINCT FAILURE PATTERNS OF MALIGNANT GLIOMAS
Authors: Seung-Won Choi, Raul Rabadan
Journal: Neuro-Oncology (2023)

Abstract Most malignant gliomas experience recurrence with distinct failure patterns. The spatial relationship between the primary and recurrent tumors usually represents the genomic distanc; however, the molecular backgrounds of these failure patterns have not been evaluated yet. Our aim was to investigate the molecular profiles underlying the distinct failure patterns of malignant gliomas. This study involved 272 malignant glioma patients, with transcriptomic data available for 166 of these cases. The failure pattern was defined according to the spatial relationship between the primary and recurrent pairs including local recurrence, remote recurrence, and leptomeningeal seeding. When the recurrent tumor exhibits more than one failure pattern simultaneously, we define this as a combined failure pattern. Local recurrence was the most frequent pattern, followed by combined failure pattern (62.9% &amp; 22.8%, respectively). Multi-variate cox analysis showed that combined failure pattern was a significant prognostic factor (odds ratio= 3.34, p-value &amp;lt; 0.001). We defined a genomic signature for malignant gliomas with a combined failure pattern (comb-GS) and validated its worse prognostic impact in other cohorts (GLASS, TCGA). Using public scRNA-seq data with regional annotation, we found that two distinct non-tumor components, immune and neuronal components, contributed to the development of the combined failure pattern. This finding was well correlated with the variability of comb-GS in different anatomic regions in IVY-gap dataset. In summary, this study demonstrated that both immune and neuronal components are involved in the progression of malignant gliomas. These two microenvironmental elements exhibit a shared negative clinical outcome, despite presenting distinct phenotype. To decipher the exact biological role of each component, experimental validation is necessary.
TMIC-43. THE IMPACT OF MICROGLIA MODULATION ON THE IMMUNE TUMOR MICROENVIRONMENT IN SYNGENEIC GLIOBLASTOMA MOUSE MODELS
Authors: Deniz Kaymak, Tala Shekarian, Marie-Françoise Ritz, Nicoletta Ferrari, Roland Kälin, Rainer Glass, Gregor Hutter
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma is exceptionally resistant to immunotherapies for which the immunosuppressive myeloid compartment is held responsible. As influencer and instructor of T-cell-immunity this compartment mainly consists of Monocyte-derived Cells (MdCs) and tissue-resident (TR) macrophages called microglia (MG). Since the response to immunotherapies depends on antigen presenting cells, we investigate this compartment and its individual role in tumor progression by genetically depleting/activating the TR MG. METHODS We made use of two MG-specific and tamoxifen inducible knockout mouse models in which 1) we activate MG by excision of the activation-repressing transcription factor Sall1 and 2) deplete MG by deleting Csf1r on MG. To investigate the effect of MG activation/depletion on the immune tumor microenvironment (iTME), immunocompetent mice were engrafted with syngeneic glioma cells and the iTME subsequently characterized by scRNAseq, spectral flow cytometry and immunofluorescence imaging. RESULTS Upon Sall1-KO, MG demonstrate a morphologically reactive phenotype. The deletion of Csf1r depletes the brain parenchyma of MG which rapidly gets repopulated by a morphologically distinct microglia-(like) population. Genetic activation of MG leads to a survival benefit in Gl261-engrafted mice compared to Cre- littermates. In contrast, depletion of MG significantly reduces the survival in Gl261 and CT-2A engrafted mice. ScRNAseq confirms the effective depletion of MG and the subsequent emergence of a MG-like cell cluster that transcriptionally remains distinct. The iTME in MG-depleted mice is characterized by a decreased abundance of exhausted and naïve CD8-Tcells and an increased infiltration of MdCs. GSEA demonstrates a dampened inflammatory profile of infiltrating MdCs. CONCLUSION The presence of MG orchestrates the development towards a more antitumorigenic iTME by shaping the antitumoral response of incoming myeloid cells and furthermore directly or indirectly influencing T-cell immunity. Understanding this interplay of MG and MdCs and its impact on instruction of antitumoral T-cell immunity could help guiding the development of novel immunotherapeutic strategies.
BIOS-03. COPY NUMBER VARIATION (CNV) AND CLINICAL OUTCOMES IN IDH-WILDTYPE VERSUS IDH-MUTANT GLIOMA
Authors: Jocelyn Chow, David Bray, Manali Rupji, Sai Mannam, Ross Greenberg, Kamaria Dansby, Stewart Neill, Jeffrey Switchenko, Kimberly Bojanowski-Hoang
Journal: Neuro-Oncology (2023)

Abstract Genomic classification of gliomas has the potential for improved prognostication and treatment guidance. However, much work remains to elucidate the full potential of genomics in glioma characterization. IDH mutant gliomas generally carry an improved survival compared to their wild-type counterparts, but their clinical course is significantly more variable and challenging to predict. The goal of this study is to characterize tumor genetic/genomic parameters associated with progression-free survival (PFS) and overall survival (OS) of both IDH-wildtype and IDH-mutant gliomas and compare the two subtypes for further stratification. We collected data for 203 patients diagnosed with IDH-wildtype gliomas (WHO Grade IV) and 88 patients with IDH-mutant gliomas (WHO Grade II-IV) from the Emory Healthcare system. Microarray single nucleotide polymorphism-copy number analysis was performed to detect total CNVs which are associated with tumor mutational burden. We analyzed total CNV based on the median, quartiles, and optimal cut points via the ideal cutpoint calculator, Cutoff Finder. We then estimated the correlation between % total CNV, PFS, and OS using the Pearson correlation coefficient. For IDH-wildtype gliomas, the mean CNV was 18.69 (standard deviation (SD): 9.62), and the median was 16.00 (IQR: 1-57). The optimal cutoff was defined as 39 for PFS analysis and 20.5 for OS analysis. For IDH-mutant gliomas, the mean CNV was 12.8 (SD: 11.36), and the median was 8.5 (IQR: 5 – 17.5). The optimal cutoff was defined as 10.5 for OS analysis and 7.5 for PFS analysis. Overall, higher CNV was associated with lower PFS and OS in both groups. However, the results were only statistically significant for OS at the optimal cutoff (20.5) for IDH-wildtype gliomas (p-value = 0.0379), and for PFS at the optimal cutoff (7.5) for IDH-mutant gliomas (p-value = 0.0420). These findings suggest that CNV may be useful as a potential prognosis factor for both tumor subtypes in different contexts.
TMIC-82. SPATIAL AND SINGLE-CELL PROTEOMIC LANDSCAPING OF THE HYPOXIC MICROENVIRONMENT IN GLIOBLASTOMA
Authors: Sheila Mansouri, Shreya Gandhi, Mark Zaidi, Olivia Singh, Shirin Karimi, Phoebe Lombard, Anna Dvorkin-gheva, Carlos Valesquez, Hafsah Ali, Kaviya Devaraja, Julio Sosa, Vikas Patil, Qinxqia Wei, Ronald Wu, Mira Li, May Cheung, Mathew Voisin, Andrew Gao, David Hedley, Kenneth Aldape, Bradley Wouters, Gelareh Zadeh
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a fatal adult solid tumour with median overall survival of 18-20 months post-diagnosis; contributing factors to therapeutic inefficacy include acquisition of genomic alterations post-therapy, immune evasion, deregulated hypervascularization, and tumor microenvironmental factors such as hypoxia. Combined with extensive inter- and intra-tumoral heterogeneity at bulk and single-cell level, hypoxia contributes to a gradient of molecular alterations that are specific to different cell populations that make up tumour bulk and reside in specific niches. Hitherto, high-dimensional histopathologic analyses of hypoxic regions within GBM tissue have not been performed. We took a combined spatial and single-cell proteomic profiling approach to investigate the histopathologic features of hypoxia by leveraging a unique clinical study wherein the exogenous hypoxia marker, pimonidazole (PIMO), was administered to GBM-patients preoperatively. Tissue specimens were subjected to imaging mass cytometry, high-resolution imaging, and serial immunohistochemistry using a panel of markers associated with cellular hallmarks of hypoxia, metabolism, proliferation, stemness, angiogenesis, and immune cell types. Our findings showed that PIMO staining is associated with histopathologic features of hypoxia and correlates with specific metabolic, immune, and stemness markers in GBM; specific lymphocyte populations were depleted from hypoxic regions alongside alterations in macrophagic and microglial landscape in a niche-specific manner; hypoxia reduced the proportion of proliferating glioma initiating cells and altered the proliferative, transcriptional, and translational capacity of different cell populations; microvessel density was reduced in hypoxic microenvironment. Cytometry by time-of-flight further validated the altered proportions of specific immune cell types enriched in hypoxic populations of GBM microenvironment. Our study is the first to report use of PIMO to interrogate spatial, single-cell, and phenotypic architecture associated with tissue hypoxia and altered expression of biomarkers associated with hypoxia/glycolysis, immune infiltration, proliferation, and stemness. Identification of targetable biomarkers and mediators of hypoxia-driven habitats in GBM may provide direction for future immunotherapeutic research.
SURG-32. EFFICACY OF LASER INTERSTITIAL THERMAL THERAPY (LITT) FOR BIOPSY-PROVEN RADIATION NECROSIS IN RADIOGRAPHICALLY RECURRENT BRAIN METASTASES
Authors: Roy Strowd, Michael Chan, Steven Tatter, Veronica Chiang, Peter Fecci, Sujit Prabhu, Constantinos Hadjipanayis, John Kirkpatrick, David Sun, Kaylyn Sinicrope, Alireza Mohammadi, Parag Sevak, Steven Abram, Albert Kim, Eric Leuthardt, Samuel Chao, John Phillips, Michel Lacroix, Brian Williams, Dimitris Placantonakis, Joshua Silverman, James Baumgartner, David Piccioni, Adrian Laxton
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Evidence is growing for the efficacy of laser interstitial thermal therapy (LITT) for radiation necrosis (RN) following stereotactic radiosurgery (SRS) for patients with brain metastases. Questions remain regarding local control, symptom control, and concurrent use of therapies. METHODS Demographics, intraprocedural data, safety, Karnofsky performance status (KPS) and survival data were prospectively collected from the LAANTERN multi-center registry (NCT02392078) then analyzed on patients consented between 2016-2020 and who were undergoing LITT for biopsy-proven RN at one of 14 U.S. centers. Data was monitored for accuracy. Statistical analysis included individual variable summaries, multivariable Fine and Gray analysis, and Kaplan Meier estimated survival. RESULTS Ninety patients met inclusion criteria. Median hospitalization time was 32.5hrs. Median time to corticosteroid cessation after LITT was 13 days (range 0 - 1229) and cumulative incidence of lesional progression was 19% at 1-year. Median post-procedure overall-survival was 2.6 years [1.7, NR] and 77% at one year as estimated by Kaplan Meier. Median KPS remained 80 through 2-year follow-up. Seizure prevalence improved from 34.4% pre-procedure to 12% 1-month post-LITT and 7.9% at 3-months. There was no significant difference in risk of radiographic progression in total and near-total ablations (91% or greater ablative coverage) versus sub-total ablations (&amp;lt; 90%). Lesion size was not a significant predictor of future radiographic progression. CONCLUSIONS LITT is an effective, minimally invasive, safe treatment for RN, in terms of both local control and symptom management. LITT is effective in the management of lesion-related seizures in addition to averting expected neurological death. LITT facilitates ongoing systemic therapy (particularly immunotherapy) by enabling the rapid cessation of corticosteroids. Effective management options for RN could facilitate the more aggressive use of combined systemic and radiotherapeutic treatment options for brain metastases patients in order to avoid failure due to tumor recurrence and extend survival.
MODL-02. DEVELOPMENT OF RODENT GLIOBLASTOMA MODELS OF MGMT-MEDIATED TEMOZOLOMIDE RESISTANCE
Authors: Teresa Lee, Deepti Bhatt, Ranjini Sundaram, W Mark Saltzman, Ranjit S Bindra, Juan C Vasquez
Journal: Neuro-Oncology (2023)

Abstract O6-methylguanine-DNA methyltransferase (MGMT) is an enzyme that repairs O6-methylguanine DNA damage lesions generated by alkylators such as temozolomide (TMZ), the standard chemotherapeutic for glioblastoma (GBM) treatment. High MGMT expression leads to TMZ resistance and is correlated with lower survival, making it an important prognostic biomarker and potential therapeutic target. Xenograft models with human GBM cell lines require implantation into immunodeficient animals, precluding the study of MGMT-dependent alkylator sensitivity in the setting of an intact tumor immune microenvironment. In this study, we developed rat and mouse glioma models of MGMT overexpression and characterized response to alkylator therapy. RG2 rat glioma and SB28 mouse glioma cells, which have low endogenous MGMT levels, were transduced with cDNA expressing FLAG-tagged MGMT to generate an isogenic pair. RG2 MGMT+ and SB28 MGMT+ cells showed robust expression of MGMT, which was effectively abrogated by MGMT inhibitors. In vitro cell viability assays showed that MGMT overexpression resulted in increased resistance to TMZ compared to parental cells, and this resistance was reversed when cells were concurrently treated with the MGMT inhibitor lomeguatrib. To model MGMT overexpression in vivo, luciferase-expressing RG2 MGMT+ cells were implanted into the brains of syngeneic Fischer 344 rats. Rats were treated with TMZ at 50mg/kg daily x 5 days via intraperitoneal injection. Tumor growth was measured by bioluminescence imaging and rats were monitored for survival and toxicity. RG2 MGMT+ tumors were highly resistant to TMZ, as treatment did not improve survival or delay tumor growth. Overall, our newly developed isogenic rat and mouse glioma models recapitulate MGMT-dependent TMZ sensitivity and provide useful preclinical tools for studying MGMT as a biomarker and potential therapeutic target in GBM. In addition, these syngeneic models facilitate studies on the immune modulation of chemotherapeutic agents in the context of MGMT expression and allows for testing of chemoimmunotherapy combinations.
TMET-20. TARGETING LINKS BETWEEN METHIONINE METABOLISM AND DNA REPAIR TO IMPROVE GBM THERAPY
Authors: Navyateja Korimerla, Kari Wilder-Romans, Jie Xu, Isra Haq, Peter Kalev, Nathan Qi, Charles Evans, Maureen Kachman, Weihua Zhou, Andrew J Scott, Ayesha Kothari, Angelica Lin, Alexandra O'Brien, Sravya Palavalasa, Erik Peterson, Marc L Hyer, Katya Marjon, Costas Lyssiotis, Taryn Sleger, Daniel Wahl
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is uniformly lethal due to intrinsic resistance to standard of care radiation (RT) and chemotherapy. Recent studies have identified altered cellular metabolism as a key mediator of GBM RT resistance. Methionine uptake is drastically elevated in GBMs compared to normal cells but whether this impacts treatment resistance is uncertain, as is the metabolic fates of methionine once it enters GBM cells. Here, we find that RT acutely increases the levels of methionine-related metabolites in a variety of RT-resistant GBM models. Stable isotope tracing studies further revealed that RT acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event through DNA damage response. We developed in vivo 13C5 methionine stable isotope tracing techniques to confirm these findings in orthotopic models of GBM. Pharmacological and dietary strategies to block methionine to SAM conversion slowed the DNA damage repair and increased cell death following RT. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase (MTAP). Pharmacologic and dietary strategies to inhibit SAM synthesis hindered tumor growth in flank and orthotopic in vivo GBM models when combined with RT. In short, these results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBM in vivo. Inhibiting the RT-induced SAM synthesis slows the DNA damage repair and augments RT efficacy in GBM. This therapeutic strategy provides scope for combining MAT2A inhibitors with RT in GBMs with impaired methionine salvage and spares the adjacent normal brain.